Abstract

Surface functionalized magnetic iron oxide nanoparticles (NPs) are a kind of novel
functional materials, which have been widely used in the biotechnology and catalysis.
This review focuses on the recent development and various strategies in preparation,
structure, and magnetic properties of naked and surface functionalized iron oxide
NPs and their corresponding application briefly. In order to implement the practical
application, the particles must have combined properties of high magnetic saturation,
stability, biocompatibility, and interactive functions at the surface. Moreover, the
surface of iron oxide NPs could be modified by organic materials or inorganic materials,
such as polymers, biomolecules, silica, metals, etc. The problems and major challenges,
along with the directions for the synthesis and surface functionalization of iron
oxide NPs, are considered. Finally, some future trends and prospective in these research
areas are also discussed.

Keywords:

Introduction

Nanoparticle are submicron moieties (diameters ranging from 1 to 100 nm according
to the used term, although there are examples of NPs several hundreds of nanometers
in size) made of inorganic or organic materials, which have many novel properties
compared with the bulk materials [1]. On this basis, magnetic NPs have many unique magnetic properties such as superparamagnetic,
high coercivity, low Curie temperature, high magnetic susceptibility, etc. Magnetic
NPs are of great interest for researchers from a broad range of disciplines, including
magnetic fluids, data storage, catalysis, and bioapplications [2-6]. Especially, magnetic ferrofluids and data storage are the applied researches that
have led to the intergration of magnetic NPs in a myriad of commercial applications.
Currently, magnetic NPs are also used in important bioapplications, including magnetic
bioseparation and detection of biological entities (cell, protein, nucleic acids,
enzyme, bacterials, virus, etc.), clinic diagnosis and therapy (such as MRI (magnetic
resonance image) and MFH (magnetic fluid hyperthermia)), targeted drug delivery and
biological labels. However, it is crucial to choose the materials for the construction
of nanostructure materials and devises with adjustable physical and chemical properties.
To this end, magnetic iron oxide NPs became the strong candidates, and the application
of small iron oxide NPs in in vitro diagnostics has been practiced for nearly half
a century [7]. In the last decade, increased investigations with several types of iron oxides have
been carried out in the field of magnetic NPs (mostly includes the Fe3O4 magnetite, FeIIFeIII2O4, ferrimagnetic, superparamagnetic when the size is less than 15 nm), α-Fe2O3 (hematite, weakly ferromagnetic or antiferromagnetic), γ-Fe2O3 (maghemite, ferrimagnetic), FeO (wüstite, antiferromagnetic), ε-Fe2O3 and β-Fe2O3) [8], among which magnetite and maghemite is the very promising and popular candidates
since its biocompatibility have already proven.

However, it is a technological challenge to control size, shape, stability, and dispersibility
of NPs in desired solvents. Magnetic iron oxide NPs have a large surface-to-volume
ratio and therefore possess high surface energies. Consequently, they tend to aggregate
so as to minimize the surface energies. Moreover, the naked iron oxide NPs have high
chemical activity, and are easily oxidized in air (especially magnetite), generally
resulting in loss of magnetism and dispersibility. Therefore, providing proper surface
coating and developing some effective protection strategies to keep the stability
of magnetic iron oxide NPs is very important. These strategies comprise grafting of
or coating with organic molecules, including small organic molecules or surfactants,
polymers, and biomolecules, or coating with an inorganic layer, such as silica, metal
or nonmetal elementary substance, metal oxide or metal sulfide. Practically, it is
worthy that in many cases the protecting shells not only stabilize the magnetic iron
oxide NPs, but can also be used for further functionalization.

In the following, we focus mainly on recent development and various strategies in
the preparation, structure and magnetic properties of various surface functionalized
strategies of magnetic iron oxide NPs and their corresponding applications, as well
as the research advances on functionalizations of magnetic iron oxide NPs worldwide.
Further the problems and major challenges still should be solved are pointed out,
and the directions in these researches are also discussed.

Synthesis of Iron Oxide NPs

In the last decades, much research has been developed to the synthesis of iron oxide
NPs, and many reports have described efficient synthesis approaches to produce the
shape-controlled, stable, biocompatible, and monodispersed iron oxide NPs. The most
common methods including co-precipitation, thermal decomposition, hydrothermal synthesis,
microemulsion, sonochemical synthesis, and sonochemical synthetic route can all be
directed to the synthesis of high quality of iron oxide NPs. In addition, these NPs
can also be prepared by the other methods such as electrochemical synthesis [9,10], laser pyrolysis techniques [11], microorganism or bacterial synthesis (especially the Magnetotactic bacteria and
iron reducing bacteria) [12,13], etc. As follows, we try to present typical and recent examples for the discussions
of each synthetic pathway and the corresponding formation mechanism.

Co-Precipitation

The most conventional method for obtaining Fe3O4 or γ-Fe2O3 is by co-precipitation. This method consists of mixing ferric and ferrous ions in
a 1:2 molar ratio in highly basic solutions at room temperature or at elevated temperature.
The size and shape of the iron oxide NPs depends on the type of salt used (such as
chlorides, sulfates, nitrates, perchlorates, etc.), the ferric and ferrous ions ratio,
the reaction temperature, the PH value, ionic strength of the media, and the other
reaction parameters (e.g. stirring rate, dropping speed of basic solution). Recently
we have reported the co-precipitation synthesis of Fe3O4 NPs and their corresponding morphology, structure, and magnetic properties at different
reaction temperature was investigated [14].

This method would critically affect the physical and chemical properties of the nanosized
iron oxide particles. Generally, the saturation magnetization (MS) values found in nanostructured materials are usually smaller than the corresponding
bulk phase, provided that no change in ionic configurations occurs [15]. Accordingly, experimental value for MS in magnetic iron oxide NPs have been reported to span the 30–80 emu g−1 range, lower than the bulk magnetic value 100 emu g−1. In addition, Fe3O4 NPs are not very stable under ambient conditions and are easily oxidised to Fe2O3 or dissolved in an acidic medium. In order to avoid the possible oxidation in the
air, the synthesis of Fe3O4 NPs must be done in an anaerobic conditions. Based on this point, Fe3O4 NPs can also be utilized to prepare the Fe2O3 NPs by oxidation or anneal treatment under oxygen atmosphere. And oxidation is not
the important influence factor for Fe2O3 NPs due to its own chemical stability in alkaline or acidic environment.

However, this method generates particles with a wide particle size distribution, which
requires secondary size selection sometimes. A wide particle size distribution will
result in a wide range of blocking temperatures (TB) due to TB depends on particle size and, therefore non-ideal magnetic behavior for many applications.
Kang et al. [16] reported a synthesis of monodispersed, uniform, and narrow size distributional Fe3O4 NPs (the diameter of NPs was 8.5 ± 1.3 nm) by co-precipitation without surfactants,
the reaction in an aqueous solution with a molar ratio of FeII/FeIII = 0.5 and a pH = 11–12, and the colloidal suspensions of the magnetite can be then
directly oxidized by aeration to form colloidal suspensions of γ-Fe2O3. In contrast, many recent publications have described efficient routes to obtain
the monodispersed NPs, surfactants such as dextran or polyvinyl alcohol (PVA) can
be added in the reaction media, or the particles can be coated in a subsequent step
[17,18]. Surfactants act as protecting agent for controlling particle size and stabilizing
the colloidal dispersions.

Additionally, the disadvantage of these aqueous solution syntheses is that the high
pH value of the reaction mixture has to be adjusted in both the synthesis and purification
steps, and the process toward uniformed and monodispersed NPs has only very limited
success. On the other hand, wastewaters with very basic pH values are also generated
in the experiment, which require subsequent treatments for protecting the environment.

Thermal Decomposition

An organic solution phase decomposition route has been widely used in iron oxide NPs
synthesis, and decomposition of Fe(cup)3(cup = N-nitrosophenylhydroxylamine), Fe(acac)3(acac = acetylacetonate), or Fe(CO)5followed by oxidation can lead to high-quality monodispersed iron oxide NPs, which
usually requires relatively higher temperatures and a complicated operation.

Sun and Zeng [19] have reported a general decomposition approach for the synthesis of size-controlled
monodispersed magnetite NPs based on high temperature (265 °C) reaction of Fe(acac)3 in phenyl ether in the presence of alcohol, oleic acid, and oleylamine. With the
smaller magnetite NPs as seeds, larger monodispersed magnetite NPs of up to 20 nm
in diameter can be synthesized and dispersed into nonpolar solvent by seed-mediated
growth method. The process does not require a size-selection procedure and is readily
scaled up for mass production. The as-synthesized Fe3O4 nanoparticle assemblies can be transformed easily into γ-Fe2O3 NPs by annealing at high temperature (250 °C) and oxygen for 2 h.

Generally, direct decomposition of Fe(Cup)3 single precursor can lead to monodispersed γ-Fe2O3 NPs [20]. The thermal decomposition of Fe(CO)5 produces iron NPs and the following oxidation by a chemical reagent can also lead
to monodispersed γ-Fe2O3 NPs [21]. For instance, Hyeon et al. [22] reported a synthesis of highly crystalline and monodispersed iron NPs without size-selection
process by the thermal decomposition of iron pentacarbonyl in the presence of oleic
acid at 100 °C. The resulting iron NPs were transformed to monodispersed γ-Fe2O3 nanocrystallites by controlled oxidation using trimethylamine oxide as a mild oxidant.
Particle size can be varied from 4 to 16 nm by controlling the experimental parameters.

Although the thermal decomposition method has many advantages for producing highly
monodispersed particles with a narrow size distribution, it has the big disadvantage
that the resulting NPs are generally only dissolved in nonpolar solvents.

Microemulsion

Microemulsion is a thermodynamically stable isotropic dispersion of two immiscible
phases (water and oil) under the surfactant present, the surfactant molecules may
form a monolayer at the interface between the oil and water, with the hydrophobic
tails of the surfactant molecules dissolved in the oil phase and the hydrophilic head
groups in the aqueous phase. As in the binary systems (water/surfactant or oil/surfactant),
self-assembled structures of different types can be formed, ranging, for example,
from (inverted) spherical and cylindrical micelles to lamellar phases and bicontinuous
microemulsions, which may coexist with predominantly oil or aqueous phases [23]. In this sense, microemulsion and inverse micelles route can be employed for obtaining
the shape- and size-controlled iron oxide NPs.

Particularly, water-in-oil (w/o) microemulsions are formed by well-defined nanodroplets
of the aqueous phase, dispersed by the assembly of surfactant molecules in a continuous
oil phase. Vidal-Vidal et al. [24] have reported the synthesis of monodisperse maghemite NPs by the one-pot microemulsion
method. The spherical shaped particles, capped with a monolayer coating of oleylamine
(or oleic acid), show a narrow size distribution of 3.5 ± 0.6 nm, are well crystallized
and have high saturation magnetization values (76.3 Am2/kg for uncoated NPs, 35.2 Am2/kg for oleic acid coated NPs, and 33.2 Am2/kg for oleylamine coated NPs). Moreover, the results show that oleylamine act as
precipitating and capping agent. However, cyclohexylamine acts only as precipitating
agent and does not avoid particle aggregation. Chin and Yaacob reported the synthesis
of magnetic iron oxide NPs (less than 10 nm) via w/o microemulsion, furthermore, in
comparison to the particles produced by Massart’s procedure [25], particles produced by microemulsion technique were smaller in size and were higher
in saturation magnetization [26].

However, despite the presence of surfactants, the aggregation of the produced NPs
usually needs several washing processes and further stabilization treatments.

Hydrothermal Synthesis

Iron oxide NPs with controlled size and shape are technologically important due to
strong correlation between these parameters and magnetic properties. The microemulsion
and thermal decomposition methods usually lead to complicated process or require relatively
high temperatures. As an alternative, hydrothermal synthesis includes various wet-chemical
technologies of crystallizing substance in a sealed container from the high temperature
aqueous solution (generally in the range from 130 to 250 °C) at high vapor pressure
(generally in the range from 0.3 to 4 MPa). This technique has also been used to grow
dislocation-free single crystal particles, and grains formed in this process could
have a better crystallinity than those from other processes, so hydrothermal synthesis
is prone to obtain the highly crystalline iron oxide NPs.

Several authors have reported the synthesis of iron oxide NPs by hydrothermal method
[27-30]. There are two major methods according to whether or not use the specific surfactants.
For example, Wang et al. [31] have reported a one-step hydrothermal process to prepare highly crystalline Fe3O4 nanopowders without using the surfactants. The nanoscale Fe3O4 powder (40 nm) obtained at 140 °C for 6 h possessed a saturation magnetization of
85.8 emu·g−1, a little lower than that of the correspondent bulk Fe3O4 (92 emu·g−1). It is suggested that the well-crystallized Fe3O4 grains formed under appropriate hydrothermal conditions should be responsible for
the increased saturation magnetization in nanosized Fe3O4. On the contrary, Zheng et al. [32] reported a hydrothermal route for preparing Fe3O4 NPs with diameter of ca. 27 nm in the presence of a surfactant, sodium bis(2-ethylhexyl)sulfosuccinate
(AOT). The magnetic properties of the NPs exhibited a superparamagnetic behavior at
room temperature.

Moreover, hydrothermal treatment is one of the successful ways of growing crystals
for iron oxide NPs. Recently Daou et al. [33] have reported that the magnetite particles with an average size of 39 nm and good
monodispersity have been synthesized by co-precipitation at 70 °C from ferrous Fe2+ and ferric Fe3+ ions by a N(CH3)4OH solution, followed by hydrothermal treatment at 250 °C. The magnetite NPs before
the hydrothermal step display an average size of 12 nm and are highly oxidized when
they are in contact with air. Additionally, hydrothermal synthesis is conductive to
prepare the unusual iron oxide nanostructures such as iron oxide nanocubes [34], iron oxide hollow spheres [35], etc.

Sonochemical Synthesis

As a competitive alternative, the sonochemical method has been extensively used to
generate novel materials with unusual properties. The chemical effects of ultrasound
arise from acoustic cavitation, that is, the formation, growth, and implosive collapse
of bubbles in liquid. The implosive collapse of the bubble generates a localized hotspot
through adiabatic compression or shock wave formation within the gas phase of the
collapsing bubble. The conditions formed in these hotspots have been experimentally
determined, with transient temperatures of 5000 K, pressures of 1800 atm, and cooling
rates in excess of 1010 K/s [36]. These extreme conditions were beneficial to form the new phase, and have a shear
effect for agglomeration, which is prone to prepare the highly monodispersive NPs.

This method has been applied for the synthesis of various nanocomposites, and its
versatility has been successfully demonstrated in iron oxide NPs preparation [37]. For instance, magnetite NPs can be simply synthesized by sonication of iron(II)acetate
in water under an argon atmosphere. Vijayakumar et al. [38] reported a sonochemical synthetic route for preparing the pure nanometer-size Fe3O4 powder with particle size of ca. 10 nm. The prepared Fe3O4 NPs are superparamagnetic and its magnetization at room temperature is very low (<1.25
emu g−1). Recently Pinkas et al. [39] developed a sonochemical synthetic method for preparing the amorphous nanoscopic
iron oxide by sonolysis of Fe(acac)3 under Ar with a small amount of added water. The organic content and the surface
area of the Fe2O3 NPs can be controlled with an amount of water in the reaction mixture, and it increases
from 48 m2 g−1 for dry solvent up to 260 m2 g−1 when wet Ar is employed. Such surface modified ultrasmall (1–2 nm) NPs exhibit an
unrecorded low magnetic transition temperature of about 25 K, below this temperature
they behave as speromagnetic, highly magnetically disordered systems with a high contribution
of the surface anisotropy, and this speromagnetic behavior can be observed by Mössbauer
spectra.

The five above mentioned synthetic methods have several advantages and disadvantages
for preparing iron oxide NPs, respectively. In terms of size and morphology control
of the iron oxide NPs, thermal decomposition and hydrothermal synthetic route seems
the optimal method. For obtaining the water-soluble and biocompatible iron oxide NPs,
co-precipitation often was employed, but this method presents low control of the particle
shape, broad distributions of sizes and aggregation of particles. As a time-competitive
alternative, sonochemical route can also be used to synthesis iron oxide NPs with
unusually magnetic properties. In addition, it is noteworthy that some green chemical
synthesis routes and biological synthesis routes have been reported for environment
protection purposes. For example, recently Bharde et al. [12] reported the bacterium Actinobacter sp. is capable of synthesizing maghemite under aerobic conditions when reacted with
the ferric chloride precursors. Moreover, maghemite NPs show superparamagnetic characteristics
as expected. Therefore, as the enviromental protection and eco friendliness-competitive
alternative, green chemistry and biological methods such as bacterially induced synthesis
based synthesis of iron oxide NPs are important advances.

In the following sections, the recent development and various strategies for obtaining
surface functionalized iron oxide NPs by organic and inorganic materials will be discussed.

Surface Functionalization by Organic Materials

In the preparation and storage of ferrofluids, the stability is of utmost importance.
Organic compounds are often employed to passivate the surface of the iron oxide NPs
during or after the preparing procedure to avoid agglomeration. The main reasons for
magnetic iron oxide NPs have hydrophobic surfaces with a large surface area-to-volume
ratio if in the absence of any proper surface coating, and the hydrophobic interactions
between the NPs will cause them to aggregate and form large clusters, resulting in
increased particle size. Additionally, in order to expand the biological application
scope of the iron oxide NPs, some biomolecules are also employed to enhance its biocompatibility.

In recent years, considerable efforts have been devoted to the design and controlled
fabrication of nanostructured materials displaying specific functional properties.
Organic compounds coated on iron oxide NPs offer a high potential application in several
areas. The structure of organic compounds functionalized magnetic iron oxide NPs consists
of two major parts: preserved the magnetic property of magnetic iron oxides and preserved
the other properties of organic molecules. Generally, if iron oxides were always assumed
as the core, its structure can roughly be divided into three types: core-shell, matrix,
and shella-core-shellb. As plotted in Fig. 1, coating an ensemble of iron oxide NPs by organic material yields core-shell nanostructure.
In these structures, the cores may be any kind of iron oxide particles, such as magnetite
or maghemite. Likewise, the shells may consist of any sort of materials including
organic ones. Matrix structure includes two typical structures: mosaic and shell-core.
Comparatively speaking, the shell-core structure consists of an organic compound NPs
core and iron oxide particle shells. Iron oxide NPs may connect with the organic core
by the interaction of chemical bonds. The mosaic structure comprising the shell layer
was made of organic molecules coated to a lot of uniformly iron oxide magnetic NPs.
Among the different matrixes that can be used to embed the NPs, polymers are of particular
interest because of their wide range of properties. Furthermore, a shell layer made
of organic molecules coated to a shell-core structurally functionalized iron oxide
NPs that will form the shella-core-shellbstructure, which occurs in many current reports and generally obtained bylayer-by-layertechnology. The shellamay be the polymer or biomolecules, likewise, the shellbcan be the same or different functional materials. Moreover, multi-component conducting
organic material systems with iron oxide NPs can be tailored to obtain desired mechanical
properties besides novel electrical, magnetic, and optical properties.

Organic compounds functionalized iron oxide NPs provide not only the basic magnetism
characteristics of magnetic NPs, but also possess good biocompatibility and biodegradability
of the functional organic materials. Moreover, organic moleculars can provide the
ensemble functional reactive group, e.g. aldehyde groups, hydroxyl groups, carboxyl
groups, amino groups, etc. It is crucial that their groups can link to the active
biosubstance such as antibody, protein, DNA, enzyme, etc., for the further application.
In the following section, the organic small molecules, macromolecules or polymer and
biological molecules functionalized iron oxide NPs and the corresponding properties
will be discussed.

Small Molecules and Surfactants

A suitable surface functionalization and choice of solvent are crucial to achieving
sufficient repulsive interactions to prevent agglomeration so as to obtain a stable
colloidal solution and further expand the scope of application. According to the surface
characteristics of the functionalized NPs, small molecules or surfactants functionalized
iron oxide NPs can be simply divided into three types: oil-soluble, water-soluble,
and amphiphilic. Oil-soluble type refers to the surface of functionalized iron oxide
NPs containing the molecular which have a weak attraction for the solvent environment,
it is generally hydrophobic group, such as the fatty acid, alkyl phenol (n = 6–10, linear or branched). Conversely, water-soluble type refers to the surface
of functionalized iron oxide NPs containing the chemical groups which have a strong
attraction for the solvent environment, it is generally hydrophilic groups, such as
the ammonium salt, polyol, lycine. Amphiphilic type refers to the surface of functionalized
iron oxide NPs containing both hydrophilic and hydrophobic chemical groups, the main
chain of these functionalized small molecules or surfactants showed concurrence of
hydrophobic and hydrophilic structural regions, which also will make the functionalized
NPs possess both oil-solubility and water-solubility, such as sulfuric lycine.

Oil-soluble type functionalization employed in order to prevent or decrease the agglomeration
of iron oxide NPs and increase the stability give rise to the monodispersity, for
instance, iron oxide NPs frequently dispersed in long-chain substance of hexadecane,
the classic example being oleic acid (CH3(CH2)7CH=CH(CH2)7CO2H), which has a C18 tail with a cis-double-bond in the middle, forming a kink. Such
kinks have been postulated as necessary for effective stabilization, and indeed stearic
acid (CH3(CH2)16CO2H) with no double-bond in its C18 tail, cannot stabilize the iron oxide NPs [7,40-42]. Additionally, Oleic acid is widely used in ferrite nanoparticle synthesis because
it can form a dense protective monolayer, thereby producing highly uniform and monodisperse
particles. However, relative to the naked iron oxide NPs, the average diameter of
functionalized NPs will increase in the range of 0–5 nm, and its saturation magnetization
(MS) almost unchanged.

Several authors have reported the magnetic iron oxide NPs coated or dispersed in the
oil-soluble organic molecules. Shaoo et al. [43] have reported the surface-coated magnetite NPs with a 6–8 nm average diameter by
oleic acid, lauric acid, dodecyl phosphonate, hexadecyl phosphonate, and dihexadecyl
phosphate etc., they found that alkyl phosphonates and phosphates could be used for
obtaining thermodynamically stable dispersions of magnetite NPs. The organic molecules’
ligands seem to form a quasi-bilayer structure with the primary layer strongly bonded
to the surface of the NPs. This study demonstrates that alkyl phosphonates and phosphates
bind efficiently to iron oxide particle surfaces, the good biocompatibility of phosphonate
and phosphate ligands may advance the utilization of encapsulated magnetic NPs in
medical applications, such as MRI and other biophysical purposes. Bourlions et al.
[44] have reported the synthesis of capped ultrafine γ-Fe2O3 NPs under anaerobic conditions by the thermal treatment of a hydrated iron(III) hydroxide
caprylate gel in boiling tetraline and by retention of the organophilic mantle around
the parent particle throughout the final solid. The capped particles, which possessed
a spherical morphology and an average size of 4 nm, were easily solvated in organic
solvents to provide stable and homogeneous magnetic organosols.

However, the oil-soluble type functionalized iron oxide NPs are relatively easy to
prepare and control. Currently the mainly research focus are the synthesis of water-soluble
type functionalized iron oxide NPs with water solubility (good disperse in aqueous
environment, can not produce agglomeration), biological compatibility (good for protein,
antibody, biotin, DNA etc., low cytotoxicity, low effect their activity), and biodegradability.
Water-soluble functionalized iron oxide NPs can be widely utilized in bioseparation
and biodetection.

Several routes were employed for obtaining the water-soluble functionalized iron oxide
NPs. One method is to directly add the biocompatible small organic molecules such
as amino acid [45], citric acid [43,46], vitamin [47,48], cyclodextrin [49-51], etc. during the synthesis procedure. Recently Xia et al. [52] reported a facile synthetic approach for preparing water-soluble Fe3O4 NPs with a surrounded layer by use of polyethylene glycol nonylphenyl ether (NP5)
and cyclodextrin (CD) in aqueous medium. Moreover, the author had also built nanostructured
spherical aggregates (mosaic type structure) from individual functionalized NPs (core-shell
type structure) and which can be tailored by the concentration of NP5 and CD. These
mesoporous aggregates of magnetite NPs can be used in magnetic carrier technology.
Though this direct method has many advantages, owing to small organic molecules do
not have good stability especially in an alkaline or acidic environment, it often
decomposes and results in the functionalized iron oxide NPs agglomeration. Furthermore,
the morphology of functionalized iron oxide NPs often presents as an aggregate clusters.

Another method is to transform the oil-soluble type into water-soluble type functionalized
iron oxide NPs, and the ligand-exchange reaction is the major approach to realize
this aim [53]. Ligand exchange is a well-known method for tuning the surface properties of NPs.
It involves adding an excess of ligand to the nanoparticle solution, which results
in the displacement of the original ligand on the NPs’ surface. Especially, ligand-exchange
reactions on noble metal NPs, via the self-assembly of thiols, have been used for
many years already [54,55]. However, more recently, several groups have reported the use of ligand exchange
to alter the surface properties of iron oxide NPs. Sun et al. [56] have prepared a monodispersed magnetite NPs with a tunable diameter range from 3
to 20 nm by the high temperature solution phase reaction of iron(III) acetylacetonate,
Fe(acac)3, with 1,2-hexadecanediol in the presence of oleic acid and oleylamine. And the hydrophobic
NPs can be transformed into hydrophilic ones by mixing with bipolar surfactants such
as tetramethylammonium 11-aminoundecanoate, allowing preparation of aqueous nanoparticle
dispersions. Subsequently, as illustrated in Fig. 2, Lattuada and Hatton [57] reported that the oleic groups initially present on the above nanoparticle surfaces
were replaced via ligand-exchange reaction with various capping agents bearing reactive
hydroxyl moieties. They also found that particle sizes in the range of 6 to 11 nm
can be tuned without using the seeded-growth process by simply varying the heating
rate of the solution containing the nucleating particles. This route was proposed
a flexible methodology for the preparation of various types of monodisperse, water-soluble
magnetic NPs coated by different polymer brushes. A similar approach was used by Fan
et al. [58] to prepare a water-dispersible γ-Fe2O3 NPs with narrow size distributions (13 ± 2 nm) via site-exchange reaction, and these
NPs were superparamagnetic and stable without aggregation in a wide range of pH 3–9.
Additionally, attachment of the biotin functionality onto the surfaces of our NPs
enabled the magnetic affinity isolation of avidin–FITC from its incubation buffer
with 96% efficiency. However, ligand-exchange reaction often contributes to the complicated
operation and the difficulty of control exchange rate, these problems are urgent to
be solved.

Moreover, the silane agent is often considered as a candidate for modifying on the
surface of iron oxide NPs directly, for the advantages of the biocompatibility as
well as high density of surface functional endgroups, and allowing for connecting
to other metal, polymer or biomolecules [59,60]. In general, silane-coated iron oxide NPs still maintains the physical characteristics
of naked NPs with high saturation magnetization, the decrease value of saturation
magnetization often less than 10 emu g−1. The 3-aminopropyltriethyloxysilane (APTES), p-aminophenyl trimethoxysilane (APTS), and mercaptopropyltriethoxysilane (MPTES) agents
were mostly employed for providing the amino and sulfhydryl group, respectively. The
physicochemical mechanism of the silane agent modifying on the surface of iron oxide
NPs according to Arkles is depicted in Fig. 3[61]. The hydroxyl groups on the iron oxide NPs surface reacted with the methoxy groups
of the silane molecules leading to the formation of Si–O bonds and leaving the terminal
functional groups available for immobilization the other substance.

Figure 3. Physicochemical mechanism for modifying the silane agents on the surface of iron oxide
NPs

We have prepared magnetite NPs with average diameter 25 ± 5 nm by modified chemical
co-precipitation, and silane bridged surface tailoring are exploited to obtain amino-coated
and thiolated magnetite NPs via corresponding APTES and MPTES modification, respectively.
The result reveals that the surface functionalized magnetic particles have a slight
dimensional increase in average diameter while retain almost original saturation magnetization;
APTES is prone to maintain the morphology of the magnetite NPs, but MPTES has an outstanding
hypochromic effect though it caused a slight decrease in the saturation magnetization.
The finding is of practical significance for magnetic NPs applications associated
with bioconjugation, target carriers, and biosensing [62]. In addition, silanes were found to render the iron oxide NPs highly stable and water-dispersible,
and it was also found to form a protective layer against mild acid and alkaline environments.
Moreover, silane ligand-exchange reaction can make the hydrophobic iron oxide NPs
into water-dispersible [63].

Polymers

Although most studies have focused on the development of small organic molecules and
surfactants coating up to now, recently polymers functionalized iron oxide NPs are
receiving more and more attention, owing to the advantages of polymers coating will
increase repulsive forces to balance the magnetic and thevan der Waalsattractive forces acting on the NPs. In addition, polymers coating on the surface
of iron oxide NPs offer a high potential in the application of several fields. Moreover,
polymer functionalized iron oxide NPs have been extensively investigated due to interest
in their unique physical or chemical properties. To make use of these materials for
fundamental or applied research, access to well-defined NPs samples whose properties
can be “tuned” through chemical modification is necessary. In a number of cases it
has now been shown that, through careful choice of the passivating and activating
polymers and/or reaction conditions, can produce NPs with tailored and desired properties.

Polymer coating materials can be classified into synthetic and natural (see Table
1). Table 1also provides a list of synthetic and natural materials that are used to functionalize
the iron oxide NPs along with their advantages, respectively. The saturation magnetization
value of iron oxide NPs will decrease after polymers functionalization.

Currently, there are two major developing directions to form polymers functionalized
iron oxide NPs, as follows: One is for the purpose of expanding application range
by introducing the functional polymers. For instance, Gupta et al. [91] have reported a microemulsion polymerization process to prepare a poly(ethyleneglycol)
(PEG)-modified superparamagnetic iron oxide NPs with magnetic core and hydrophilic
polymeric shell. Highly monodispersed iron oxide NPs were synthesized by using the
aqueous core of aerosol-OT (AOT)/n-Hexane reverse micelles (without microemulsions) in N2 atmosphere. The average size of the PEG-modified NPs was found to be around 40–50
nm with narrow size distribution. It is important that the cytotoxicity profile of
the NPs on human dermal fibroblasts as measured by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay showed that the particles are nontoxic and may be useful for various
in vivo and in vitro biomedical applications. Another is for the purpose of manufacturing
a monodisperse NPs with well-defined shape and a controlled composition. Monomer polymerization
method or in-suit synthesis in the microporous of polymeric microsphere was employed
for obtaining the uniform magnetic composite NPs with high content of iron oxide NPs
[92]. As Zhang et al. [93] reported, an approach employs polymer microgels as templates for the synthesis of
iron oxide NPs. At first, precursor cations were incorporated into the poly(N-isopropyl acrylamide-acrylic acid-2-hydroxyethyl acrylate) microgel particles crosslinked
with NN’-methylene bisacrylamide (BIS), then iron oxide NPs were in-suit synthesized in the
microgel by co-precipitation. They show that NPs with predetermined dimensions and
size-dependent properties can be synthesized by using a very delicate balance between
the reaction conditions, the composition and the structure of microgel templates,
and the concentration of NPs in the microgel. The synthesis of superparamagnetic Fe3O4 NPs in the microgel templates was extremely efficient: for NPs concentration as high
as 0.724 g per gram polymer, the NPs had an average size of ca. 8.1 nm, low polydispersity,
and showed excellent magnetic properties, while the microspheres carrying these NPs
remained stimuli-responsive. Additionally, atom transfer radical polymerization (ATRP)
method was utilized for obtaining monodisperse NPs with well-defined core-shell shape.
ATRP can offer polymeric shells with low polydispersity and this method is easy to
control the molecular weight, thereby, the thickness of the polymeric shell. Recently
several polymer-coated iron oxide NPs through surface-initiated ATRP in polar solvents
were successfully developed [94-97]. ATRP can be used in preparing polymers with narrow molecular weight distribution,
block copolymers, graft polymers, random copolymers and finally to realize controlling
the thickness of the polymeric shell and the size of polymer functionalized iron oxide
NPs. As illustrated in Fig. 4, Sun et al. [98] have reported the synthesis of the iron oxide/polystyrene (PS) core/shell NPs via
surface initiated ATRP. At first a method was employed to covalently bond initiators
onto the surface of iron oxide NPs, which was the combination of ligands exchange
reaction and condensation of triethoxysilane having an ATRP initiating site, 2-bromo-2-methyl-N-(3-(triethoxysilyl)propyl)
propanamide. Then the polystyrene shell was grafted from the initiating sites on the
surface of iron oxide NPs through ATRP. The covalently bonded polymeric shell could
prevent the undesired site exchange of the MNPs surface functionalities. From the
as-synthesized macroinitiators, the polymer functionalized iron oxide NPs with a well-defined,
covalently bonded PS shell have been successfully prepared through the surface initiated
ATRP, which exhibits a characteristic of a controlled/”living” polymerization.

Moreover, polymer are often employed to make up the deficiency of small organic molecules
and surfactant for the purpose of obtaining the surface functionalized iron oxide
NPs. Therefore, besides the above research focus, how to prepare the functionalized
iron oxide NPs with ideal chemical stability and good biocompatibility remains the
great challenges. The right choice of organic materials can provide a structure suitable
for obtaining the well-controlled functionalized NPs. For example, Frankamp et al.
[99,100] developed an approach for direct controlling the magnetic interaction between iron
oxide NPs through dendrimer-mediated self-assembly. The resulting assemblies featured
systematically increasing average interparticle spacing over a 2.4 nm range with increasing
dendrimer generation. This increase in spacing modulated the collective magnetic behavior
by effective lowering of the dipolar coupling between the particles. The dependence
of blocking temperature on interparticle spacing was found to point toward a much
more dramatic interdependence at close interparticle spacing, and a weaker correlation
at larger spacing. Overall, the development of other methods for constructing the
surface engineering of iron oxide NPs is of great important.

Biological Molecules

Various biological molecules such as protein [101,102], polypeptide [103], antibody [104,105], biotin and avidin [106], etc., may also be bound to the surface of iron oxide NPs directly or indirectly
by chemically coupling via some functional endgroups to make the NPs target specific.
The biological molecules functionalized iron oxide NPs will greatly improve the particles’
biocompatibility. Such magnetic NPs can be very useful to assist an effective separation
of proteins, DNA, cells, biochemical products, etc.

With appropriate surface chemistry, biomolecules can immobilize on iron oxide NPs.
Zhang et al. [107] have reported a microemulsion approach to prepare a human serum albumin (HAS)-coated
Fe3O4 magnetic NPs as a radioisotope carrier labeled with 188Re and explored the optimal labeling conditions with 188Re. The procedure for preparing HAS-coated Fe3O4 magnetic NPs as follows: With cotton oil as oil phase, a mixture of HSA and magnetite
solution as water phase and Span-83 as emulsion agent. The mixture of the above two
solutions was ultrasonicated for 15 min, then added rapidly dropwise into cotton oil
at 130 °C under stirring condition. The diameter of HSA-coated magnetic NPs was about
200 nm. The particles can be labeled with 188Re for the purpose of in vivo regional target therapy.

In contrast, the major strategy for surface functionalization by biological molecules
includes two steps, first synthesizing the small molecules or polymers functionalized
NPs, and then coupled to the biomolecules by chemical bond or physical adsorption.
Recently, Lee et al. [108] developed a route for conjugating the γ-Fe2O3 NPs with single strand oligonucleotides. The water-soluble magnetic NPs with carboxyl
groups on their surfaces were prepared at first, and then by using 1-ethyl-3-(3-dimrthylaminopropyl)carbodiimide
hydrochloride (EDC) as a liker reagent, they successfully modified a protein, streptavidin,
on the surface of γ-Fe2O3 NPs. Streptavidin functionalized Fe2O3 can catch a biotin-labeled single strand oligonucleotides through the strong affinity
between streptavidin and biotin.

Additionally, superparamagnetic iron oxide core of individual NPs becomes more efficient
at dephasing the spins of surrounding water protons, enhancing spin−spin relaxation
times (T2 relaxation times) so that the NPs act as magnetic relaxation switches (MRS) [109]. Based on this phenomenon, Perez and colleagues [110] have developed biocompatible magnetic nanosensors that act as MRS to detect molecular
interactions in the reversible self-assembly of disperse magnetic particles into stable
nanoassemblies recently. MRS technology can be used to detect different types of molecular
interactions (DNA-DNA, protein-protein, protein-small molecule, and enzyme reactions)
with high efficiency and sensitivity using magnetic relaxation measurements MRI. Furthermore,
the magnetic changes are detectable in turbid media and in whole-cell lysates without
protein purification. The developed magnetic nanosensors can be used in a variety
of biological applications such as in homogenous assays, as reagents in miniaturized
microfluidic systems, as affinity ligands for rapid and high-throughput magnetic readouts
of arrays, as probes for magnetic force microscopy, and potentially for in vivo imaging.
For instance, oligonucleotides functionalized iron oxide NPs aggregate in the presence
of target oligonucleotides (20 pM limit), resulting in a measurable increase (30 ms)
in the T2 relaxation times of the surrounding water. It was further discovered that base pair
insertions in the target strand resulted in only 2–5 ms increases in the relaxation
times, while single base pair mismatches resulted in 1–21 ms increases in T2, indicating that these systems could potentially be used to selectively detect DNA
mutations.

Surface Functionalization by Inorganic Materials

Although there have been many significant progresses in the synthesis of organic materials
functionalized iron oxide NPs, simultaneous control of their shape, stability, biocompatibility,
surface structure, and magnetic properties is still a challenge. As an alternative,
inorganic compound functionalized iron oxide NPs can greatly enhance the antioxidation
properties for naked iron oxide NPs, and its corresponding scope of application has
been greatly extended. Moreover, inorganic compounds functionalized iron oxide NPs
are very promising for application in catalysis, biolabeling, and bioseparation. The
applied coating inorganic materials include silica, metal, nonmetal, metal oxides,
and sulfides. Composite NPs can roughly be divided into two major parts: preserved
the magnetic property of iron oxides and preserved the other properties of inorganic
materials.

With controlled structure and interface interactions, nanocomposites can exhibit novel
physical and chemical properties that will be essential for future technological applications.
As illustrated in Fig. 5, if iron oxides were always assumed as the core, the structure of inorganic compound
functionalized iron oxide NPs can roughly be divided into five types: core-shell,
mosaic, shell-core, shell-core-shell, and dumbbell. Many studies have shown that in
the presence of core-shell structure composite NPs, such as Fe3O4@Au NPs, its two-layer structure include magnetite core and gold shell in the outer
layer. Generally, superparamagnetic colloid particles offer some attractive possibilities
in bioseparation or biodetection, they should be made at dimensions they are comparable
to those of a virus (20–500 nm), a protein (5–50 nm), or a DNA (10–100 nm). Nevertheless,
the reactivity of iron oxide NPs has been shown to greatly increase as their dimensions
are reduced, and particles with relatively small sizes may undergo rapid biodegradation
when they are directly exposed to biological environments. Therefore, matrix-dispersed
iron oxide NPs can be prepared in a variety of different states and greatly increase
the size of naked iron oxide NPs, the three representative states have been shown
in Fig. 5. The mosaic structure are commonly produced in the hollow silica spheres with iron
oxide NPs, and the shell-core structure can be formed by individual iron oxides which
are connected their inner layer. Additionally, shella-core-shellbtype composite NPs can be obtained bylayer-by-layertechnology and also can be overcome the above limitations. The shellamay be the metal NPs, polymer, and quantum dots, likewise, the shellbcan be the same or different functional materials. This type of composite NPs is expected
to greatly expand the application scope of iron oxide NPs. Dumbbell structure is commonly
formed through epitaxial growth of iron oxide (or inorganic compound NPs) on the inorganic
compound seeds (or ion oxide NPs), and finally obtained the bifunctional composite
NPs.

This section, the interest arises from the possibility of combining the magnetic and
the other properties by entrapping magnetic iron oxide NPs in the other inorganic
compound layers, or by connecting magnetic iron oxide NPs with the other inorganic
materials. We enumerate some typical and recent examples for the discussions of each
feasible method and the corresponding properties and application of composite NPs.

Silica

Silica is the most common compound for preparing the functionalized iron oxide NPs,
silica-coated iron oxide NPs have several advantages as follows: (a) this coating
provides not only the stability to the iron oxide NPs in solution, but also avoids
the interparticle interactions and prevent agglomeration generating, (b) this composite
NPs possess a good biocompatibility, hydrophilicity and stability, and (c) the technology
of preparation for size tunable composite NPs is already mature, and its variation
of the shell thickness is relatively easy to control. In addition, silica-coating
helps in binding the various biological or the other ligands at the NPs surface for
various applications. For instance, Ashtari et al. [111] have reported an effective method for recovery of target ssDNA based on amino-modified
silica-coated Fe3O4 NPs.

At present, the Stöber methods, sol–gel process, and aerosol pyrolysis are the prevailing
choices for coating iron oxide NPs with silica. In general, silica coating will increase
the size of particles and the magnetic properties of composite NPs also will change.
It is noteworthy that silica thickness from 5 to 200 nm can be tuned by varying the
concentration of ammonia and the ratio of tetraethoxysilane (TEOS) to water, moreover,
silica coating was easily preformed on the iron oxide NPs’ surface through hydroxyl
groups in the aqueous environment, especially using the Stöber method and sol–gel
process. This resulted in better dispersion and less aggregation of the magnetic particles.
The current research focus is further extended the function of silica functionalized
iron oxide NPs, and obtains the magnetic composites with tunable structure and good
dimension stability.

Therefore, for further extended function of silica functionalized iron oxide NPs,
some quantum dots and other optical materials have been introduced. Ma et al. [112] reported a synthesis of FexOy@SiO2 core-shell NPs by the sol–gel and modified Stöber methods. Superparamagnetic iron
oxide NPs are first coated with silica to isolate the magnetic core from the surrounding.
Subsequently, the dye molecules are doped inside a second silica shell based on which
the dye molecules are adopted inside to improve photostability and allowed for versatile
surface functionalities. The result have shown that the saturation magnetization (MS) was decreased about 35 emu·g−1 with a shell thickness of 10–15 nm after silica coating, the blocking temperature
(TB) and the coercivity (Hc) were also decreased. Yi et al. [113] have developed a pathway to synthesize magnetic quantum dots (QD) based on silica
coating nanocomposite of maghemite NPs and CdSe quantum dots (SiO2/γ-Fe2O3-CdSe, ca. 50–80 nm in size). Figure 6 shows the schematic and TEM images for synthesis of SiO2/γ-Fe2O3-CdSe nanocomposite. The images clearly indicate the iron oxides and quantum dots
with silica coating. And author claims that the presence of CdSe quantum dots increased
the effective magnetic anisotropy of the γ-Fe2O3-containing NPs. The nanocomposites preserved the magnetic property of γ-Fe2O3 and optical property of CdSe quantum dots.

Figure 6. Schematic for SiO2/MP-QD nanocomposites synthesis (left); TEM micrographs of aγ-Fe2O3 MPs; b SiO2/MP; c interconnected MPs and CdSe QDs (after 8 h of SiO2/MP-QD reaction); de SiO2/MP-QD nanocomposites (after 48 h of SiO2/MP-QD reaction; note the presence of both Fe2O3 MPs and CdSe QDs (finer crystallites denoted by arrows in panel e)); and f SiO2/MP-QD nanocomposites formed at a lower CdSe concentration (0.5 mg/mL of cyclohexane);
g High resolution TEM micrograph of the area marked by the arrow in (f), showing the presence of CdSe QDs and γ-Fe2O3 MPs. From [113]

For obtaining the magnetic composites with tunable structure and good dimension stability
still remains challenges, many skillful approaches have successfully been employed.
Lu et al. [114] reported a sol–gel procedure that leads to uniform silica-coated iron oxide NPs,
and their shell thickness can be adjusted by controlling the amount of precursors
(TEOS) added to the 2-propanol solution. Fluorescent dyes have also been incorporated
into the silica shells by covalently coupling these organic compounds with the sol–gel
precursor. These multifunctional NPs are potentially useful in a number of areas because
they can be simultaneously manipulated with an externally applied magnetic field and
characterized in situ using conventional fluorescence microscopy. An alternative method
to prepare these NPs with uniform silica shells and tailored thickness is to use microemulsion
method, also known as the water-in-oil (W/O) microemulsion process, which has three
primary components: water, oil, and surfactant [115]. Homogeneous SiO2-coated Fe2O3 core-shell NPs with controlled silica shell thickness from 1.8 to 30 nm had been
synthesized by reverse microemulsion [116].

The aerosol pyrolysis method has recently arisen as a facile, rapid method to obtain
NPs with relevant properties. Especially, by taking advantage of the subtle interplay
between the parameters controlling NPs formation in aerosol process, it is possible
to obtain either a continuous, three-dimensional network of particles (present a matrix
structure) or a hollow structure. Moreover, aerosol pyrolysis has also been used for
silica coating, but the structure of composite NPs commonly is the mosaic type, such
as hollow silica spheres with iron oxide shells. Taetaj et al. [117,118] described this method for the synthesis of superparamagnetic hollow silica spheres
and the shell containing γ-Fe2O3 nanocrystals with the size range from 4 to 10 nm. The spherical composites were prepared
by aerosol pyrolysis of a methanol solution containing tetraethoxysilane and iron
nitrate and further annealing in a conventional furnace. And it was observed that
the blocking temperature (TB) strongly depends on nanocomposite size, the enhancement of the effective magnetic
anisotropy with respect to the bulk γ-Fe2O3 can be considered as coming fundamentally from surface anisotropy [119].

From the above examples, it can be seen that silica functionalized iron oxide NPs
is a facile process. In this case, great progress in the field of silica-coated iron
oxide NPs have been made, some research results have also being transformed into commercial
application [120,121].

Metal or Nonmetal

Another facile route to protect the iron oxide NPs is to induce a controlled oxidation
of a pure single-metal or nonmetal shell, such as gold, silver, platinum, palladium,
iron, carbon etc. The control of the single-metal or nonmetal layer has a tremendous
impact on the scope of iron oxides’ application, particularly to expand its scope
of biomedical and catalyst application. For instance, gold is often employed to passivate
the surface of magnetite NPs to avoid oxidation. We need to notice that the gold,
silver, and carbon single-metal functionalization will conduce the descend of the
iron oxide NPs’ saturation magnetization (Ms) value, but the result of cobalt, platinum, copper, palladium single-metal functionalization
may be opposite, depending on the mass magnetic susceptibility (χ) value of the used
materials. In addition, the diameter of metallic or nonmetallic functionalized iron
oxide NPs is prone to tailoring, and the necessary diameter can be obtained by controlling
the reduction and repeat times.

In general, there are two ways for preparing the metal functionalized iron oxide NPs,
one is direct reduction of the single-metal ions on the surface of iron oxide NPs.
Mandal et al. [122] have reported that the Fe3O4 NPs were separated, coated with noble metal gold and silver by directly reducing
the Au+ and Ag+, respectively, to achieve stability of the magnetic NPs for a long time, this route
yielded structures of size from 18 to 30 nm, although the author claims that the NPs
possess a well-defined core-shell structure, the TEM micrograph of samples cannot
directly reflect. Data also showed that the saturation magnetization (Ms) of gold-coated is 38 emu g−1 (T = 10 K) and it is reduced by 57.6% from the bulk Fe3O4 NPs (92 emu g−1T = 10 K). Generally, this method often applies to prepare the core-shell type composite
NPs, but it is prone to maintain the magnetic properties of naked iron oxides.

On the other hand, the most common route was employed for preparing the metallic functionalized
iron oxide NPs by reduction of the single-metal ion on the surface of the small molecule,
polymer or SiO2 functionalized iron oxide NPs. Several authors have reported the magnetic iron oxide
NPs coated with gold. Gold coatings provide not only the stability to the NPs in solution,
but also helps in binding the biological molecule which include -SH group at the NPs
surface for various biomedical applications. Recently we [123] have adopted this approach to prepare the monodispersed gold-coated Fe3O4 NPs via sonolysis of a solution mixture of gold ions and amino-modified Fe3O4 NPs with further drop-addition of reducing agent. The composite NPs with diameter
of 30 nm and their saturation magnetization (Ms) was 63 emu g−1 (T = 300 K), and it is reduced only by ca. 0.03% from the bulk Fe3O4 NPs (65 emu g−1T = 10 K). Therefore, this route was beneficial to maintain the saturation magnetization
(Ms) of the original bare magnetite NPs. Yu et al. [124] also reported a synthesis of dumbbell-like bifunctional Au-Fe3O4 NPs by epitaxial growth of iron oxides on the Au seeds. A mixture, consisting of
Au NPs, Fe(CO)5, 1-octadecene solvent, oleic acid, and oleylamine, was heated and refluxed at 300
°C followed by room temperature oxidation under air. In this way, dumbbell-like NPs
were obtained with tunable sizes in the range 3–14 nm. As illustrated in Fig. 7, Stoeva et al. [125] skillfully used shell-core type functionalized iron oxide NPs (SiO2/Fe3O4 NPs) that electrostatically attract 1–3 nm gold-nanoparticle seeds which act in a
subsequent step as nucleation sites for the formation of a continuous gold shell around
the shell-core NPs upon HAuCl4 reduction. The author also demonstrates that these three-layer magnetic NPs can be
functionalized with DNA following synthetic methods for pure gold NPs and reversibly
assembled into macroscopic aggregates using complementary linking oligonucleotides.
Additionally, Teng et al. [126] have reported a one-pot sequential synthetic method for the synthesis of well-defined
and shell-thickness-tunable Pt@Fe2O3 core-shell NPs. These Pt@Fe2O3 core-shell NPs could have potential applications in catalysis and as precursors for
making property-tunable magnetic NPs, thin films, and nanocomposites.

Figure 7. Synthetic scheme for the preparation of the three-layer NPs (left); TEM images of colloids after each synthetic step. ab SiO2 particles covered with silica-primed Fe3O4 NPs (SiO2–Fe3O4). cd SiO2 particles covered with silica-primed Fe3O4 NPs and heavily loaded with Au nanoparticle seeds (SiO2–Fe3O4–Au seeds). e Three-layer magnetic NPs synthesized in a single-step process from particles presented
in (c) and (d). Note the uniformity of the gold shell. The inset shows the three-layer magnetic
NPs drawn to the wall with a magnet. From [125]

Taking into account the application prospects of magnetic record and magnetic ink
materials recently, most studies have focused on the development of carbon-coated
iron oxide magnetic NPs (such as carbon-encapsulated magnetic NPs), the carbon shell
not only protected the iron oxide NPs from rapidly degraded by environment, but it
also prevented the NPs’ agglomeration caused by van der Waals attraction. Though carbon-coated will cause the reduction of saturation magnetization,
the other magnetic properties will change little. Moreover, carbon functionalized
iron oxide NPs have many advantages over the other materials, such as much higher
chemical and thermal stability as well as biocompatibility. Recent methods offer new
alternatives for the controlled synthesis of novel, stable, and functional iron oxides/C
NPs. Wang et al. [127] reported the preparation of Fe3O4/C nanocomposition by heating the aqueous solution of glucose and oleic acid-stabilized
magnetite NPs. Dantas et al. [128] reported the synthesis of iron oxides/C composites, and it can be used in the treatment
of textile waste water as heterogeneous catalysts in the Fenton reaction. Though carbon-coated
iron oxide NPs have many advantageous properties, the synthesis of monodispersed composite
NPs in isolated from is currency one of challenges in this field.

Furthermore, single-metal functionalized iron oxide NPs (especially noble metal functionalized
iron oxide NPs, and mostly take the direct method by reducing the single-metal ions
on the surface of iron oxide NPs) also used as catalysts, such as Au/Fe2O3 catalyst for CO oxidation [129,130], Au/α-Fe2O3 catalyst for water-gas shift reaction [131,132], Fe3O4/Pd nanoparticle-based catalyst for the cross-coupling of acrylic acid with iodobenzene
[133] and decarboxylative coupling reaction in aqueous media [134], Ag-Fe3O4 catalyst for epoxidation of styrene [135], etc. These heterogeneous catalysts with a matrix structure generally as the magnetically
recyclable catalysts (MRCs) are developed in recent years and can be very useful to
assist an effective separation and recovery in a liquid-phase reaction by a magnet,
especially when the catalysts are in the nanometer-sized range and possess higher
activities than their pure and bulk single-metal or nonmetal counterparts [136,137]. Therefore, the development of the facile and rapid methods for the preparation of
efficient MRCs is still a challenge.

Hence, many efforts have been made for getting the nanometer-sized MRCs with high
activity and easy separation properties. For example, a Au/FexOy catalyst with high CO oxidation activities at low temperature prepared by deposition–precipitation
(DP) method was reported by Lin and Chen [138]. In this work, the size and surface area of MRCs can be adjusted by the PH value
during the DP process and the calcination temperature. Moreover, after 90 min time
on stream, the conversion of CO can be reached 100%. Additionally, a comparative study
results by Avgouropoulos et al. [139] shows that the Au/α-Fe2O3 catalyst is superior to the Pt/γ-Al2O3 and Cuo-CeO2 for the selective CO oxidation at relatively low reaction temperatures (<80–120 °C,
depending on contact time and feed composition employed). As illustrated in Fig. 8, Jiang et al. [140] have reported a indirect route for preparing the Fe3O4@SiO2-Gn-PAMAM-Pd(0) matrixs composites (n = 0–4, where n is the generation of the dendrimer, abbreviated as Gn, the MRCs possess a high conversion
>99.5%) and their applications as MRCs for the hydrogenation of allyl alcohol. Pd
NPs with diameters of about 2.5 nm were stabilized homogeneously on the surface of
Fe3O4@SiO2-Gn-PAMAM and the sizes of the magnetic composite NPs are about 60–100 nm. These characteristics
of the systems lead to the high catalytic activity for hydrogenation of allyl alcohol,
and the rate of the reaction can also be controlled by changing the generation of
PAMAM. The silica in the system may physically protect the Fe3O4 core apart from corruption in the reaction environments and the surface functional
groups may contact PAMAM tightly.

Recently common materials coated on the surface of iron oxide NPs are receiving more
attention, because it usually imports metal oxides’ special properties. Li et al.
[149] reported a chemical displacement procedure that leads to air-stable Fe3O4@Al2O3 core-shell NPs. The NPs are rather uniform and they claim that it with captured phosphopeptides
were directly deposited on the MALDI (matrix-assisted laser desorption/ionization)
target for analysis due to its high magnetic response. Hong et al. [150] reported ZnO-coated magnetite core-shell NPs were obtained by coating the Fe3O4 NPs with direct precipitation using zinc acetate and ammonium carbonate. They claim
that the functionalized NPs’ antioxidation ability is much better than the naked Fe3O4 NPs. However, the particles obtained are not very uniform and its saturation magnetization
(Ms) decrease from 67.78 to 20.33 emu/g.

Magnetic materials coated on the iron oxide NPs usually have a dramatic influence
on the magnetic properties. The combination of two different magnetic phases will
lead to new functionalized iron oxide NPs, with many possible applications. Cheon
et al. [6,151] reported the fabrication of highly ordered binary Fe3O4@CoFe2O4 NPs by superlattices transition; the preparation process shows a unique ferrimagnetic
phase transformation behavior through nanoscale redox chemical reactions, the particles’
saturation magnetization have been greatly enhanced, and its coercivity (HC) increased from 580 to 15,000 Oe.

In addition, optical and electrical materials functionalized iron oxide NPs obviously
enable the enlargement of the iron oxide NPs’ application scope. For example, Wang
et al. introduced the superparamagnetic γ-Fe2O3 beads-CdSe@ZnS quantum dots NPs prepared by thiol–metal bonds conjunction, and their
average diameter of this luminescent/magnetic nanocomposite was ca. 20 nm, and it
exhibited high emission quantum yield and, was easily separated from solution by magnetic
decantation using a permanent magnet. The NPs were used in cell separation and would
be used in a variety of bioanalytical assays involving luminescence detection and
magnetic separation [152]. Recently Li et al. [153] reported a synthesis of Fe3O4@TiO2 composite NPs by a indirect route that involves three steps (Fig. 9). First, magnetite NPs were synthesized via a solvothermal reaction, using FeCl3 as the source of magnetite, and ethylene glycol as both the solvent and reductant.
Then, the magnetite NPs were coated with a thin layer of carbon by the polymerization
and carbonization of glucose through a hydrothermal reaction, resulting in Fe3O4@C NPs. Finally, tetrabutyltitanate was pre-hydrolyzed and absorbed onto the composite
NPs, and eventually converted into titania by calcination under nitrogen. Moreover,
this composite NPs can be used for selective enrichment of phosphopeptides easily
in phosphoproteome analysis as it possesses the magnetic properties [154]. In addition, Chen et al. [155] have reported the functional Fe3O4/TiO2 core/shell magnetic NPs can be as photokilling agents for pathogenic bacteria. Therefore,
more and more optical and electrical materials functionalized materials functionalized
iron oxide NPs have been employed for the biological technology.

Figure 9. Scheme of the synthetic route to Fe3O4@TiO2 core-shell NPs. From [153]

Conclusions and Future Outlook

Although in this review there are various strategies for obtaining the functionalized
iron oxide NPs, the results have shown that three major effectivenesses as follows:
(a) Improves the biocompatibility and chemical stability, and tailors the dispersibility
and water solubility; (b) Endows the iron oxide new physico-chemical properties, such
as magnet-optical properties, magnetic-electrical properties, magnetic-thermal properties,
etc.; (c) Provides the iron oxide new functional endgroups for the subsequent functionalized
procedures or the subsequent applications, such as conjugation with the DNA, antibody,
protein, etc.

In the coming years, despite all the recent progresses made, it is still a challenge
to be faced that synthesis of high-quality functionalized magnetic iron oxide NPs
with a tunable sizes and shapes in a controlled manner. Moreover, synthesis and surface
engineering of iron oxide NPs involves complex chemical, physical, and physicochemical
multiple interactions, it is the another challenge to understand the synthetic mechanisms
detailedly. However, the magnetic properties and function of naked or surface functionalized
iron oxide NPs depend upon their physical properties: the size and shape, their microstructure,
and the chemical phase in which they are present [156]. Luckily, several physicochemical techniques have been developted to determine these
parameters.

Therefore, how to improve the stability and availability of functionalized iron oxide
NPs in extreme environmental conditions, how to develop an efficient and orderly magnetic
micro- or nano-assembly structures, and how to realize large-scale or industrial synthesis,
these problems are urgent to be solved for obtaining a ideal functionalized iron oxide
materials.

For all that, we still believe the surface functionalization and modification of magnetic
iron oxide NPs to introduce additional functionality will attract more and more attention.
Furthermore, multifunctional magnetic iron oxide composite nanoparticle systems with
designed active sites will promise for a various applications, such as catalysts,
magnetic recording, bioseparation, biodetection, etc. The future work in this area
must be focused on the research of the toxicity and degradability of naked or surface
functionalized iron oxide NPs, and preparing it via green chemistry for reducing the
environmental pollution as much as possible. Successful development in this area will
aid the growth of the various scientific researches or industrial applications as
well as improving the quality of life in the population.

Acknowledgments

W. Wu thanks all the colleagues during past collaborations at the HUT who have contributed
to the work described here: Lei Zeng, Jingke Huang, Rong Hu and Professors Jianxin
Tang and Hong Chen. This review is a dedication to all of them.